Pain has a great impact on the physical physiological functions and mental state of patients and reduces their QOL (Quality Of Life) due to its severity. The number of patients with chronic pain in the world is reported to exceed 20 million, and the overall market size of medicines for pain treatment in Japan, the U.S. and Europe is said to be about 2 trillion yen. In addition, the number of patients with diseases which may cause pain, such as cancer, stroke, diabetes and AIDS, has been increasing, and under such circumstances, the establishment of an appropriate treatment strategy for pain is a very important medical issue. Particularly, neuropathic pain is less sensitive to nonsteroidal antiinflammatory drugs and narcotic analgesics, and more effective medicines for neuropathic pain are expected to be increasingly desired. However, the pathogenesis of neuropathic pain is diverse and the underlying molecular mechanism is very complicated. Therefore, the medicine for radical treatment of neuropathic pain is yet to be developed (Non Patent Literature 1). Clarifying the molecular mechanism of the development and maintenance of neuropathic pain and thereby advancing the development of breakthrough medicines for neuropathic pain is one of the biggest medical issues in the 21st century.
One of the causes of neuropathic pain is thought to be plastic changes in neural circuits in the dorsal horn, which is present in the dorsum of the spinal cord (Non Patent Literature 2). Sensory inputs from the periphery undergo various processing, such as amplification, attenuation and integration, in the dorsal horn of the spinal cord and are delivered to the brain. Peripheral nerve injuries reportedly induce plastic changes in neural network in the dorsal horn of spinal cord, for example abnormal axon collateral formation and enhanced synaptic transmission, leading to the development of pain (Non Patent Literature 3). Therefore, clarifying the molecular mechanism which regulates the plasticity of neural network in the dorsal horn is expected to advance the development of a novel pain therapy.
Netrin-4 is one of the secretory proteins belonging to the netrin family. Netrin-4 has a structure very similar to that of the β chain of extracellular-matrix laminin, and is known to have various roles including those associated with neurite formation, cell migration, cell survival, angiogenesis, cancer cell growth, etc. (Non Patent Literature 4). However, there is no research report on the role of netrins in the adult spinal cord, and it is completely unknown whether netrins are associated with the pathogenesis of pain.